Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex

Marianne Hoogeveen-Westerveld, Rosemary Ekong, Sue Povey, Izabela Karbassi, Sat Dev Batish, Johan T. den Dunnen, Agnies van Eeghen, Elizabeth Thiele, Karin Mayer, Kira Dies, Li Wen, Catherine Thompson, Steven P. Sparagana, Peter Davies, Cora Aalfs, Ans van den Ouweland, Dicky Halley, Mark Nellist

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Previously, we demonstrated that pathogenic amino acid substitutions in the N-terminal domain of TSC1 (amino acids 50-224) are destabilizing. Here we investigate an additional 21 unclassified TSC1 variants. Our functional assessment identified four substitutions (p.L61R, p.G132D, p.F158S, and p.R204P) between amino acids 50 and 224 that reduced TSC1 stability and prevented the TSC1-TSC2-dependent inhibition of TORC1. In four cases (20%), our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our new data confirm our previous finding that the N-terminal region of TSC1 is essential for TSC1 function.

Original languageEnglish (US)
Pages (from-to)476-479
Number of pages4
JournalHuman Mutation
Volume33
Issue number3
DOIs
StatePublished - Mar 2012

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Tuberous Sclerosis
Amino Acid Substitution
Amino Acids
Genes
Software
Mutation
mechanistic target of rapamycin complex 1

Keywords

  • Hamartin
  • TSC1
  • TSC2
  • Tuberin
  • Tuberous sclerosis complex

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Hoogeveen-Westerveld, M., Ekong, R., Povey, S., Karbassi, I., Batish, S. D., den Dunnen, J. T., ... Nellist, M. (2012). Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex. Human Mutation, 33(3), 476-479. https://doi.org/10.1002/humu.22007

Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex. / Hoogeveen-Westerveld, Marianne; Ekong, Rosemary; Povey, Sue; Karbassi, Izabela; Batish, Sat Dev; den Dunnen, Johan T.; van Eeghen, Agnies; Thiele, Elizabeth; Mayer, Karin; Dies, Kira; Wen, Li; Thompson, Catherine; Sparagana, Steven P.; Davies, Peter; Aalfs, Cora; van den Ouweland, Ans; Halley, Dicky; Nellist, Mark.

In: Human Mutation, Vol. 33, No. 3, 03.2012, p. 476-479.

Research output: Contribution to journalArticle

Hoogeveen-Westerveld, M, Ekong, R, Povey, S, Karbassi, I, Batish, SD, den Dunnen, JT, van Eeghen, A, Thiele, E, Mayer, K, Dies, K, Wen, L, Thompson, C, Sparagana, SP, Davies, P, Aalfs, C, van den Ouweland, A, Halley, D & Nellist, M 2012, 'Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex', Human Mutation, vol. 33, no. 3, pp. 476-479. https://doi.org/10.1002/humu.22007
Hoogeveen-Westerveld M, Ekong R, Povey S, Karbassi I, Batish SD, den Dunnen JT et al. Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex. Human Mutation. 2012 Mar;33(3):476-479. https://doi.org/10.1002/humu.22007
Hoogeveen-Westerveld, Marianne ; Ekong, Rosemary ; Povey, Sue ; Karbassi, Izabela ; Batish, Sat Dev ; den Dunnen, Johan T. ; van Eeghen, Agnies ; Thiele, Elizabeth ; Mayer, Karin ; Dies, Kira ; Wen, Li ; Thompson, Catherine ; Sparagana, Steven P. ; Davies, Peter ; Aalfs, Cora ; van den Ouweland, Ans ; Halley, Dicky ; Nellist, Mark. / Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex. In: Human Mutation. 2012 ; Vol. 33, No. 3. pp. 476-479.
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